Abstract

OBJECTIVE:

To use a combined neurogenetic-neuroimaging approach to examine the functional consequences of preclinical dopaminergic nigrostriatal dysfunction in the human motor system. Specifically, we examined how a single heterozygous mutation in different genes associated with recessively inherited Parkinson disease alters the cortical control of sequential finger movements.

METHODS:

Nonmanifesting individuals carrying a single heterozygous Parkin (n = 13) or PINK1 (n = 9) mutation and 23 healthy controls without these mutations were studied with functional MRI (fMRI). During fMRI, participants performed simple sequences of three thumb-to-finger opposition movements with their right dominant hand. Since heterozygous Parkin and PINK1 mutations cause a latent dopaminergic nigrostriatal dysfunction, we predicted a compensatory recruitment of those rostral premotor areas that are normally implicated in the control of complex motor sequences. We expected this overactivity to be independent of the underlying genotype.

RESULTS:

Task performance was comparable for all groups. The performance of a simple motor sequence task consistently activated the rostral supplementary motor area and right rostral dorsal premotor cortex in mutation carriers but not in controls. Task-related activation of these premotor areas was similar in carriers of a Parkin or PINK1 mutation.

CONCLUSION:

Mutations in different genes linked to recessively inherited Parkinson disease are associated with an additional recruitment of rostral supplementary motor area and rostral dorsal premotor cortex during a simple motor sequence task. These premotor areas were recruited independently of the underlying genotype. The observed activation most likely reflects a "generic" compensatory mechanism to maintain motor function in the context of a mild dopaminergic deficit.

Figure 1 Experimental design (A) and main effect of motor task (B)(A) Experimental design. The fMRI session consisted of 10 alternating periods without movements (REST) or sequential movements (TASK). Each block lasted for 24 seconds. There were 10 blocks of TASK and 10 blocks of REST. A two-dimensional drawing of the palm of the right hand was continuously presented in the center of the visual field throughout the fMRI session. During the REST periods, the line drawing of the hand was continuously presented but without dots. Participants were instructed to remain still and fixate the hand with their eyes. During each block of TASK, participants performed three motor sequences. Each sequence consisted of three thumb-to-finger opposition movements. At the onset of each movement trial, the index, middle, ring, or little finger was labeled with a red dot on a two-dimensional drawing of the palm of the right hand. The position and order of the red dot specified the motor sequence that had to be performed within a given trial. When the instruction cue disappeared from the screen, participants sequentially tapped with the tip of their right thumb onto the tip of the indicated fingers. They were asked to move at a convenient speed and to perform the task as accurately as possible. (B) Main effect of the motor task. The axial slices show the motor regions that showed a task-related increase in BOLD signal during the sequential finger movement task. The statistical parametric maps are superimposed onto a T2-weighted structural MRI template provided by MRIcro (http://www.sph.sc.edu/comd/rorden/mricro.html). The voxels of the activation maps are color-coded according to their Z values and thresholded at p < 0.05 using the FWE method as implemented in SPM2.

Figure 2 Regional increases in task-related blood oxygen level–dependent (BOLD) signal changes in nonmanifesting carriers of aParkinorPINK1mutation(A) Statistical parametric maps. Sagittal, coronal, and axial slices highlighting those voxels in the pre–supplementary motor area (SMA) and adjacent dorsal premotor cortex (PMd) that showed a relative increase in BOLD signal during the sequential finger movement task in mutation carriers relative to controls without a mutation. The statistical parametric maps are superimposed onto a T2-weighted structural MRI template provided by MRIcro (http://www.sph.sc.edu/comd/rorden/mricro.html). The voxels of the activation maps are color-coded according to their Z values. For illustrative purposes, the maps are thresholded at an uncorrected p value of p < 0.01. (B) Parameter estimates of task-related BOLD signal changes in the right and left pre-SMA and right dorsomedial PMd. The column plots give the mean β values (as estimated by the general linear model) for the task-related change in BOLD signal during the sequential finger movement task for each of the four groups (red columns = mutation carriers; yellow columns = non–mutation carriers). The β values are given in arbitrary units (AU) and refer to the voxel showing a peak difference between mutation carriers and noncarriers. Error bars equal the 95% confidence interval of the mean.